This proposal addresses the hypothesis that with growth and development there are changes in the normal electrophysiologic, autonomic, metabolic and structural characteristics of the heart, all of which alter the response of the heart to pathological processes and to pharmacologic agents. As a result, we believe that the changes in expression of disease processes as well as the responses of the heart to potentially therapeutic interventions that occur with age are conditioned in part by the developmental stage of the end organ (the heart) as well as by those structures that influence the heart (autonomic nervous system and hormones) and by those processes that control drug interaction with the heart. Hence the theme focuses on a developmental approach to cardiac arrhythmias and their therapy. The approach is multifaceted in that a variety of electrophysiologic, biochemical, pharmacological and ultrastructural techniques will be used. Although the overall approach is to study growth and development throughout the spectrum of life, the most intensive area of investigation is centered on the neonatal, young and adolescent stages. The research is incorporated into 6 Projects and the overall hypothesis tested recurs in the electrophysiological, biochemical, autonomic and clinical studies, as well as in Core C (ultrastructure). Two additional cores provide administrative (A) and tissue culture (B) support. The significance of these studies is that they provide an alternative method to the standard approaches for considering arrhythmias, their genesis and treatment. Using the information obtained about developmental changes in function and structure we can only improve our understanding of the mechanisms responsible for arrhythmias but can design and seek new means for their prevention and treatment.